Preoperative anxiolysis in pediatric population: A comparative study between oral midazolam and oral ketamine.

CONTEXT: Preoperative anxiety is synonymous with pediatric surgery. Anxiolysis is of crucial importance and poses a significant challenge to the pediatric anesthesiologist. Orally administered midazolam and ketamine can be used as anxiolytic premedication in children. AIM: To compare the efficacy of orally administered midazolam and ketamine for preoperative sedation and anxiolysis in children and determine the minimum interval required between premedication and parental separation. SETTING AND
DESIGN: Prospective, randomized, double-blind study.
MATERIALS AND METHODS: A total of 70 children aged 2-8 years, belonging to ASA grade 1 and 2, scheduled to undergo elective infraumbilical and peripheral surgeries were randomized into two groups of 35 each to receive either midazolam (0.5 mg/kg) or ketamine (5 mg/kg) orally. They were assessed at an interval of 5 minutes up to 40 minutes, at the time of parental separation, intravenous cannulation, and application of face mask for ventilation. Sedation was noted according to Ramsay Sedation Scale and anxiolysis was noted according to Anxiolysis Scores used in previous published studies. STATISTICAL ANALYSIS USED: Skewed data between groups were analyzed by Mann Whitney U Test. Data within a group were analyzed using Friedman's Analysis of variance and a post hoc test.
RESULTS: No statistically significant difference in sedation and anxiolysis scores were obtained between the groups at any point of time. Maximum sedation score was achieved at 20 minutes in both the groups, with no statistically significant difference with scores obtained thereafter. Statistically significant difference occurred in anxiolysis score at study points in group receiving midazolam.
CONCLUSION: The study documents the rapid achievement of preoperative sedation and anxiolysis in children with orally administered midazolam or ketamine, with the latter producing a superior quality of anxiolysis. An interval of 20 minutes is sufficient between premedication and parental separation.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Surgery and anesthesia exert an immense emotional stress on both parents and children. The preoperative period in children is fraught with extreme anxiety and emotional stress, most of which arises from fear of the unknown. Behavioral and physiological measures of anxiety have identified anesthetic induction as the most stressful point during the entire preoperative period[1] in children. Preoperative anxiety causes adverse neuroendocrine responses, which not only prove deleterious in the immediate postoperative period, but often persist into the future as post-traumatic stress disorder.[2] Thus, allaying this anxiety is of utmost importance for providing a calm and pleasant anesthetic experience and preventing an adverse impact on the psychological milieu of the child in future. This can be accomplished with a careful preoperative visit and sedative premedication. Non-pharmacologic methods like preoperative preparation programs, parental presence during anesthetic induction, and preoperative interview have been advocated in the past without much success. However, premedication with sedatives has been shown to be most effective, especially for those at a higher risk of developing extreme anxiety and distress by establishing mental and physical relaxation, reducing sensory input, metabolic rate, and antagonizing adverse reaction of the autonomic nervous system.[3] The ideal premedication in children should be acceptable, rapid, and reliable in onset, have minimal side effects, rapid elimination, and an atraumatic route of administration. Several drugs have been studied in the past, each with its pros and cons. Oral transmucosal fentanyl has been used but not without the risk of respiratory depression, unpleasant dysphoria, nausea, and vomiting in young children.[4] Chloral hydrate syrup has been popular in the past till three cases of mortality following drug overdose was reported in 1993.[5] The past few years have witnessed a novel approach in pediatric premedication, with numerous studies depicting the role of orally administered midazolam and ketamine for the purpose.

Midazolam is a water-soluble benzodiazepine with greater amnestic than sedative potential.[6] Oral midazolam syrup has been found to produce sedation and anxiolysis at a dose of 0.25 mg/kg with minimal effects on ventilation and oxygen saturation even at a dose of 1 mg/kg (maximum 20 mg).[7] Ketamine acts at the thalamoneocortical projection to produce dose-dependent sedation and dissociative anesthesia. Oral ketamine produces predictable satisfactory sedation and anxiolysis without significant side effects like respiratory depression or emergence delirium in children.[8]

The aim of this study is to evaluate the differences in quality of premedication, if any, with orally administered midazolam and ketamine in the pediatric population undergoing infraumbilical and peripheral surgeries under general anesthesia and ascertain the minimum interval required between premedication and parental separation.

MATERIALS AND METHODS

This present study was a prospective, randomized, double-blind, parallel group study to compare the sedative and anxiolytic efficacy of orally administered midazolam and ketamine as premedication in children. Seventy patients aged 2 to 8 years belonging to ASA Class 1 and 2 undergoing elective infraumbilical and peripheral surgeries participated in this study between May 2010 and April 2011. All subjects were free of allergy to study drugs, hemodynamic instability, and comorbidities pertaining to the respiratory, cardiovascular, renal, and nervous system. The patients’ parents received a complete description of the study and a written informed consent was subsequently obtained. The study was approved by the Institutional ethics committee and was carried out in the pediatric surgery operating room of a large teaching hospital serving as a tertiary center of care. Children were equally divided by random selection using random number tables between the study groups to receive either oral midazolam 0.5 mg/kg (5 mg/ml parenteral formulation; Group M) or oral ketamine 5.0 mg/kg (50 mg/ml parenteral formulation; Group K). Both medications were diluted in clear apple juice to make a net volume of 5 ml, mixed thoroughly and administered to the children by their parents. If the premedication was not completely ingested or retained, that child was excluded from further analysis. Demographic data were recorded. Sedation was assessed at baseline (before premedication), followed by an interval of 5 minutes up to 40 minutes at which child was separated from its parents to be taken to the operating room for anesthetic induction. Anxiolysis was assessed at parental separation, at intravenous cannulation, and at application of face mask. Sedation was assessed according to the Ramsay Sedation Scale[9] and anxiolysis was assessed by means of scores used in previously published studies.[10] In the operating room, a cannula was inserted into a peripheral vein and anesthesia was induced with intravenous dose of thiopentone 5 mg/kg and glycopyrrolate 0.01 mg/kg followed by Atracurium 0.5 mg/kg to facilitate endotracheal intubation. Anesthesia was maintained with halothane, at an inspired concentration titrated to stable vital signs, in 66% nitrous oxide in oxygen. If cannulation was resisted by the child, it was done after induction of anesthesia with inhalational anesthetic technique. The lungs were ventilated mechanically. At the conclusion of surgery, all anesthetic drugs were discontinued simultaneously and the trachea extubated at resumption of spontaneous ventilation and return of reflexes. Diclofenac sodium suppository was administered as analgesic of choice. Child was observed in PACU for a period of 24 hours.

RESULTS

Data were described using Tulsa, Oklahoma: Stat Soft, Inc. (2001) STATISTICA (data analysis software system) Version 6. Normally distributed numerical variables in the two groups were analyzed using Student's unpaired t-test, whereas other numerical variables were analyzed by Mann-Whitney U test. Categorical variables between the two groups were analyzed by Fisher's exact test and Chi square test. Intra-group variation was analyzed by Friedman's Analysis of Variance. A P value of < 0.05 was considered statistically significant.

Table 1 describes the demographic characteristics of the study subjects. Group M (n = 35) had a mean ± S.D age of 4.67 ± 2.19 years, weight of 14.75 ± 4.83 kg with 26 male and 9 female children. Group K (n = 35) had a mean ± S.D age of 5.42 ± 1.94 years, weight of 16.42 ± 4.23 kg with 30 male and 5 female children. Statistically significant difference in demographic variables between the study groups was absent. Baseline vital parameters (heart rate, systolic, diastolic, and mean blood pressure) are depicted in Table 2, with no statistically significant difference obtained between the two groups by virtue of Students unpaired t test, 2 tailed. To compare the sedative efficacy of midazolam and ketamine, Mann Whitney U Test was applied as the data were not normally distributed. Table 3 and Figure 1 denote the sedation scores between the two groups over the study period. No statistically significant difference in the scores at any point of time was obtained between the groups. Intra-group variation in sedation score over time was analyzed by Friedman's ANOVA followed by a post hoc test and is depicted in Figures 2A and B. In both the study groups, the mean ± S.D sedation scores progressively increased from baseline post-premedication with a maximum score achieved at 20 minutes (P < 0.001). The sedation score at 20 minutes ceased to have any statistically significant difference with scores obtained thereafter in either group (P > 0.05). Group M had a mean ± S.D sedation score of 1.97 ± 0.45 at baseline and 2.91 ± 0.37 at 20 minutes. Group K had a mean ± S.D sedation score of 1.85 ± 0.42 at baseline and 3.08 ± 0.70 at 20 minutes. Mean ± S.D sedation scores at 40 minutes post-premedication was 3.22 ± 0.64 and 3.54 ± 0.78 in Group M and Group K, respectively. Comparison of anxiolysis scores at various points between the study groups was obtained by Chi square test. No statistically significant difference in the anxiolysis scores was obtained between the groups at parental separation, intravenous cannulation, and mask application, as depicted in Tables 4–6. Friedman's ANOVA followed by a post hoc test was used to analyze the intra-group variation in anxiolysis scores over the study points in either group, as denoted in Table 7 and Figure 3. The anxiolysis score at parental separation had a statistically significant difference with that at intravenous cannulation and mask application in Group M (P < 0.05). Mean ± S.D of anxiolysis score was 1.31 ± 0.58, 2.05 ± 1.02, and 1.97 ± 1.09 at parental separation, intravenous cannulation, and mask application, respectively. Group K exhibits a greater constancy in the anxiolysis scores over the study points with no statistically significant difference between the scores obtained (P > 0.05). Mean ± S.D of anxiolysis scores was 1.25 ± 0.65, 1.71 ± 0.92, and 1.68 ± 1.02 at parental separation, intravenous cannulation, and mask application, respectively.

Table 1

Demographic variables

Table 2

Comparison of preoperative variables by 2 tailed students unpaired T test

Table 3

Comparison of sedation score (Ramsay sedation scale) between the two groups at various time points

Figure 1

Comparison of variation of sedation score over time between group M and K

Figure 2

(a) Variation in sedation score over time within group M (b) Variation in sedation score over time within group K

Table 4

Comparison of anxiety score at parental separation between the two groups

Table 6

Comparison of anxiety score at mask application between the two groups

Table 7

Comparison of anxiety scores between the two groups over time

Figure 3

Comparison of variation in anxiety score at different points of time between group M and K

DISCUSSION

The most important finding of this study conducted on Indian children posted for infraumbilical or peripheral surgery under general anesthesia was that a single oral dose of the parenteral formulation of either midazolam or ketamine was effective in rapidly producing similar degree of preoperative sedation and anxiolysis, with a superior quality of anxiolysis produced by the latter drug. This study found that oral midazolam and ketamine induce rapid and dramatic sedative and anxiolytic response, which was statistically significant from baseline to 20 minutes post-premedication and was well sustained with no further statistically significant difference through the remaining study period till parental separation occurred at 40 minutes post-premedication. Such a rapid and effective response free of adverse effects like respiratory depression, nausea, and vomiting with a single oral administration has seldom been reported with any other drug previously used for premedication in children.

In our study, most children in either group became drowsy or asleep (achieved sedation score of 3 or more) by 20 minutes of administration of the drug (80% in group M and 88% in group K). This finding was consistent with the conclusion drawn by Alderson and Lerman[11] who had concluded that within 20 minutes of administration of the premedication, sedation in the two groups was similar and most children became drowsy (P < 0.001). However, according to their study, a sedation score of greater than 3 was never achieved, i.e., no child fell asleep in either group. In our study, at 40 minutes, about 95% of subjects in either group were drowsy or asleep. Of them, 48.5% and 11.2% were in light and deep sleep, respectively, in group M and 35% were calm or apprehensive. In Group K, 17.14% and 5.71% were in light and deep sleep, respectively, and 72% were calm or apprehensive. This difference with Alderson and Lerman[11] may have been because they had measured the maximum sedation at 20 minutes from administration of premedication.

In our study, the degree of anxiolysis achieved by both the drugs did not have any statistically significant difference with respect to the anxiolysis scores, this finding being consistent with that of Alderson and Lerman[11] and Kumar and coworkers.[12] However, the quality of anxiolysis achieved by oral ketamine was better as evidenced by the greater constancy in the anxiolysis scores over the different study points beyond parental separation at intravenous cannulation and mask application. This particular finding has not been portrayed by any previous study on this subject and may be considered quite remarkable. Keeping in view this specific clinical finding, it may be concluded that a superior quality of preoperative anxiolysis can be achieved by orally administered ketamine as the internal surroundings of the operating room poses a greater threat to children since parental presence at that point is seldom possible. Moreover, induction of anesthesia being the most stressful event in the entire perioperative period, an agent that maintains an optimum degree of sedation and anxiolysis till that very point is always preferable.

The real strength of this study rests in documenting the rapid sedative and anxiolytic effect of oral midazolam and ketamine in the Indian pediatric population for premedication highlighting the aspect that superior quality of anxiolysis is achieved by ketamine.

However, several limitations do exist and the results of this preliminary study should be interpreted cautiously, as the sample size was randomized and the results might not be applicable to all age groups of the pediatric population, since age-specific changes in the pharmacokinetics of midazolam have known to occur.[13]

Table 5

Comparison of anxiety score at intravenous cannulation between the two groups